Genes that influence LIN-12/Notch Activity in C. elegans

LIN-12/Notch蛋白是介导细胞-细胞相互作用的受体，其在细胞生长期间指定细胞命运。 动物发展。LIN-12/Notch蛋白的研究直接关系到理解分子生物学的发展。 两种严重而常见的人类疾病的潜在机制。LIN-12/Notch的组成型激活 鱼藤蛋白与人类患者和哺乳动物中某些癌症的发生有关。 模型，LIN-12/Notch信号转导通路的关键组分presenUin的活性是 对阿尔茨海默病的发展至关重要。其他不太常见的疾病也与 在LIN-12/Notch通路组分中存在畸变。 我们在C.秀丽隐杆线虫的研究有助于我们了解 LIN-12/Notch蛋白的发育作用和分子机制。这项建议涉及到 鉴定和表征影响C.优雅我们的第一个具体目标 包括基于抑制相关表型的已证实的遗传筛选的新变异， 具有组成性lin-12激活[lin-12（d）等位基因]。我们的第二个具体目标涉及基本的 新的sel [lin-12的抑制/增强]基因的表征，我们的第三个具体目标是关注 了解我们发现的新基因是如何协同工作的最后两个具体目标涉及 在外阴前体细胞特化过程中LIN-12介导的侧向信号传导。第四个目标是 识别和表征LIN-12在该信号传导事件中的配体，并且第五个目的涉及 通过表征可能参与Ras介导的外阴诱导和 LIN-12介导的侧向信号传导。 当这些具体目标完成后，我们希望已经确定了保守的成分， 阐明了LIN-12/Notch信号在动物体内调节和执行的基本机制 发展

LIN-12/Notch proteins are receptors that mediate cell-cell interactions that specify cell fate during animal development. Studies of LIN-12/Notch proteins are directly relevant to understanding the molecular mechanisms underlying two serious and common human diseases. Constitutive activation of LIN-12/Notch _roteins has been associated with the development of certain cancers in human patients and in mammalian models, and the activity of a key component of the LIN-12/Notch signal transduction pathway, presenUin, is central to the development of Alzheimer's disease. Other, less common, diseases have also been associated with aberrations in LIN-12/Notch pathway components. Our work on lin-12 in C. elegans has contributed to the current state of understanding of conserved developmental roles and molecular mechanisms of LIN-12/Notch proteins. This proposal is concerned with identifying and characterizing new genes that influence lin-12 activity in C. elegans. Our first specific aim encompasses new variations on a proven genetic screen, based on suppression of phenotypes associated with constitutive lin-12 activation [lin-12(d) alleles]. Our second specific aim is concerned with the basic characterization of new sel [suppressor/enhancer of lin-12] genes, and our third specific aim is concerned with understanding how the new genes we identify work together. The last two specific aims are involved with the LIN-12-mediated lateral signalling during vulval precursor cell specification. The fourth aim is concerned with identifying and characterizing the ligand for LIN-12 in this signalling event, and the fifth aim is concerned with characterizing a gene that may be involved in the interplay between Ras-mediated vulval induction and LIN-12-mediated lateral signalling. When these specific aims are completed, we hope to have identified conserved components and illuminated fundamental mechanisms of the regulation and execution of LIN-12/Notch signalling in animal development.